Natural killer (NK) cells play an important role in controlling cancer, infectious diseases, transplant rejection, autoimmune diseases, and the like. Receptor molecules, namely killer cell immunoglobulin-like receptors (hereinafter, referred to as KIRs) are present on the surface of NK cells. KIRs are very highly polymorphic and make up one of the paired receptor family which is a family consisting of inhibitory type receptors and activating type receptors. The activation of NK cells depends on a ratio of expression level of inhibitory type KIRs and activating type KIRs and the presence of ligands on target cells. Further, the KIR family share high sequence homology in the extracellular domain; and it is often the case that the inhibitory type KIR and the activating type KIR recognize an identical ligand.
KIR2DS1 which is the activating type KIR makes up the paired receptor family with KIR2DL1 which is the inhibitory type KIR. KIR2DS1 controls the activation of NK cells by recognizing some HLA-Cs, which are the same ligands as KIR2DL1, and unknown non-self ligands.
Virus-infected cells and tumor cells express the KIR2DS1 ligand and are thereby recognized by NK cells; and activated NK cells try to remove those virus-infected cells and tumor cells. Meanwhile, an inappropriate immune response originating from excessive activation of NK cells is involved in autoimmune diseases and transplant rejection.
For the purpose of activating NK cells, clinical applications using an antibody that recognizes the inhibitory type KIR have been under way; and several reports have come out.
Patent Literature 1 to 3 disclose an antibody that binds to KIR2DL1, KIR2DL2, and KIR2DL3. In addition, Non Patent Literature 1 to 3 disclose an antibody that binds to KIR2DL1, KIR2DL2, and KIR2DL3 to exhibit inhibitory effects, namely IPH2101. To be more specific, Non Patent Literature 1 describes a phase I clinical trial of IPH2101 for acute myeloid leukemia; Non Patent Literature 2 describes a phase I clinical trial of IPH2101 for multiple myeloma; and Non Patent Literature 3 describes combined effects of IPH2101 and lenalidomide on multiple myeloma. In addition, Non Patent Literature 4 and 5 disclose an antibody that binds to KIR2DL1, KIR2DL2, and KIR2DL3 to exhibit inhibitory effects, namely 1-7F9.